RESUMEN
Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiologíaRESUMEN
Alvocidib (AVC; flavopiridol) is a potent cyclin-dependent kinase inhibitor used in patients with acute myeloid leukemia (AML). The FDA has approved orphan drug designation to AVC for treating patients with AML. In the current work, the in silico calculation of AVC metabolic lability was done using the P450 metabolism module of the StarDrop software package, that is expressed as a composite site lability (CSL). This was followed by establishing an LC-MS/MS analytical method for AVC estimation in human liver microsomes (HLMs) to assess metabolic stability. AVC and glasdegib (GSB), used as internal standards (IS), were separated utilizing a C18 column (reversed chromatography) with an isocratic mobile phase. The lower limit of quantification (LLOQ) was 5.0 ng/mL, revealing the sensitivity of the established LC-MS/MS analytical method that exhibited a linearity in the range 5-500 ng/mL in the HLMs matrix with correlation coefficient (R2 = 0.9995). The interday and intraday accuracy and precision of the established LC-MS/MS analytical method were -1.4% to 6.7% and -0.8% to 6.4%, respectively, confirming the reproducibility of the LC-MS/MS analytical method. The calculated metabolic stability parameters were intrinsic clearance (CLint) and in vitro half-life (t1/2) of AVC at 26.9 µL/min/mg and 25.8 min, respectively. The in silico results from the P450 metabolism model matched the results generated from in vitro metabolic incubations; therefore, the in silico software can be used to predict the metabolic stability of the drugs, saving time and resources. AVC exhibits a moderate extraction ratio, indicating reasonable in vivo bioavailability. The established chromatographic methodology was the first LC-MS/MS method designed for AVC estimation in HLMs matrix that was applied for AVC metabolic stability estimation.
Asunto(s)
Microsomas Hepáticos , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Microsomas Hepáticos/metabolismo , Reproducibilidad de los ResultadosRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super-enhancers (SE) play important roles in controlling tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin-dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE-mediated, tumor-specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE-mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.
Asunto(s)
Antineoplásicos , Leucemia-Linfoma de Células T del Adulto , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Genes Relacionados con las Neoplasias , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Antineoplásicos/farmacología , Elementos de Facilitación Genéticos , Regulación Leucémica de la Expresión GénicaRESUMEN
The primary cilium provides cell sensory and signaling functions. Cilia structure and function are regulated by ciliogenesis-associated kinase 1 (CILK1). Ciliopathies caused by CILK1 mutations show longer cilia and abnormal Hedgehog signaling. Our study aimed to identify small molecular inhibitors of CILK1 that would enable pharmacological modulation of primary cilia. A previous screen of a chemical library for interactions with protein kinases revealed that Alvocidib has a picomolar binding affinity for CILK1. In this study, we show that Alvocidib potently inhibits CILK1 (IC50 = 20 nM), exhibits selectivity for inhibition of CILK1 over cyclin-dependent kinases 2/4/6 at low nanomolar concentrations, and induces CILK1-dependent cilia elongation. Our results support the use of Alvocidib to potently and selectively inhibit CILK1 to modulate primary cilia.
Asunto(s)
Cilios , Ciliopatías , Cilios/metabolismo , Ciliopatías/metabolismo , Flavonoides/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , PiperidinasRESUMEN
Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.
Asunto(s)
Citarabina , Leucemia Mieloide Aguda , Humanos , Citarabina/efectos adversos , Leucemia Mieloide Aguda/patología , Daunorrubicina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inducción de Remisión , JapónRESUMEN
For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically cytarabine and daunorubicin (the 7 + 3 regimen). One broad spectrum drug, flavopiridol (also known as Alvocidib) has shown significant activity against AML through the inhibition of cyclin-dependent kinases. Flavopiridol is a semisynthetic flavonoid and our research team recently described methods to formulate another flavonoid, quercetin, through the ability of flavonoids to bind divalent metals. This method relies on use of copper-containing liposomes to enhance the apparent solubility of flavopiridol and to create formulations suitable for intravenous (i.v.) use. Similar to quercetin, flavopiridol is defined as an aqueous-insoluble compound (< 1 mg/mL in water) and this research sought to evaluate whether the copper-binding capabilities of flavopiridol could be used to prepare an injectable formulation that would exhibit enhanced exposure and improved efficacy. Flavopiridol powder was added directly to preformed copper-containing liposomes (DSPC:Chol or DSPC:DSPE-PEG2000) and the resulting formulations were characterized. Pharmacokinetic and efficacy studies were then conducted. The liposomal flavopiridol formulations were well-tolerated in mice following i.v. administration at a dose of 5 mg/kg with no apparent acute or chronic toxicities. In vivo pharmacokinetics of the optimized DSPC/DSPE-PEG2000 liposomal flavopiridol formulation demonstrated a 30-fold increase in AUC (0.804 µg-hr/mL versus 26.92 µg-hr/mL) compared to the free flavopiridol formulation. The resultant liposomal formulation also demonstrated significant therapeutic activity in MV4-11 and MOLM-13 subcutaneous AML models. Additional studies will be required to define whether formulation changes can be made to enhance flavopiridol retention in the selected composition. The results suggest that further increases in flavopiridol retention will result in improved therapeutic activity.
Asunto(s)
Leucemia Mieloide Aguda , Animales , Citarabina , Flavonoides , Leucemia Mieloide Aguda/tratamiento farmacológico , Liposomas , Ratones , PiperidinasRESUMEN
BACKGROUND: Cytarabine (ara-C) is the major drug for the treatment of acute myeloid leukemia (AML), but cellular resistance to ara-C is a major obstacle to therapeutic success. The present study examined enhanced anti-apoptosis identified in 3 newly established nucleoside analogue-resistant leukemic cell line variants and approaches to overcoming this resistance. METHODS: HL-60 human AML cells were used to develop the ara-C- or clofarabine (CAFdA)-resistant variants. The Bcl-2 inhibitor venetoclax and the Mcl-1 inhibitor alvocidib were tested to determine whether they could reverse these cells' resistance. RESULTS: A 10-fold ara-C-resistant HL-60 variant, a 4-fold CAFdA-resistant HL-60 variant, and a 30-fold CAFdA-resistant HL-60 variant were newly established. The variants demonstrated reduced deoxycytidine kinase and deoxyguanosine kinase expression, but intact expression of surface transporters (hENT1, hENT2, hCNT3). The variants exhibited lower expression of intracellular nucleoside analogue triphosphates compared with non-variant HL-60 cells. The variants also overexpressed Bcl-2 and Mcl-1. Venetoclax as a single agent was not cytotoxic to the resistant variants. Nevertheless, venetoclax with nucleoside analogs demonstrated synergistic cytotoxicity against the variants. Alvocidib as a single agent was cytotoxic to the cells. However, alvocidib induced G1 arrest and suppressed the cytotoxicity of the co-administered nucleoside analogs. CONCLUSIONS: Three new nucleoside analogue-resistant HL-60 cell variants exhibited reduced production of intracellular analogue triphosphates and enhanced Bcl-2 and Mcl-1 expressions. Venetoclax combined with nucleoside analogs showed synergistic anti-leukemic effects and overcame the drug resistance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Clofarabina/uso terapéutico , Citarabina/uso terapéutico , Flavonoides/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proliferación Celular , Clofarabina/farmacología , Citarabina/farmacología , Flavonoides/farmacología , Humanos , Piperidinas/farmacología , Sulfonamidas/farmacologíaRESUMEN
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, affecting approximately 21,000 people annually (nearly 11,000 deaths) in the United States. B-cell lymphoma 2 (BCL-2) family proteins, notably myeloid cell leukemia-1 (MCL-1), have been associated with both the development and persistence of AML. MCL-1 is one of the predominant BCL-2 family members expressed in samples from patients with untreated AML. MCL-1 is a critical cell survival factor for cancer and contributes to chemotherapy resistance by directly affecting cell death pathways. Here, we review the role of MCL-1 in AML and the mechanisms by which the potent cyclin-dependent kinase 9 inhibitor alvocidib, through regulation of MCL-1, may serve as a rational therapeutic approach against the disease.
RESUMEN
Cyclins and cyclin-dependent protein kinases (CDKs) are important proteins that are required for the regulation and expression of the large number of components necessary for the passage through the cell cycle. The concentrations of the CDKs are generally constant, but their activities are controlled by the oscillation of the cyclin levels during each cell cycle. Additional CDK family members play significant roles in a wide range of activities including gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1-phase of the cell cycle produce D type cyclins that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Subsequently, CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factor, which in turn lead to the biosynthesis of dozens of proteins required for cell cycle progression. Consequently, cells pass the G1-restriction point and are committed to complete cell division in the absence of mitogenic stimulation. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S-, G2-, and M-phase progression. A crucial mechanism in controlling cell cycle progression is the precise timing of more than 32,000 phosphorylation and dephosphorylation reactions catalyzed by a network of protein kinases and phosphoprotein phosphatases as determined by mass spectrometry. Increased cyclin or CDK expression or decreased levels of endogenous CDK modulators/inhibitors such as INK4 or CIP/KIP have been observed in a wide variety of carcinomas, hematological malignancies, and sarcomas. The pathogenesis of neoplasms because of mutations in the CDKs are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Palbociclib, ribociclib, and abemaciclib are FDA-approved CDK4/6 inhibitors used in the treatment of breast cancer. These drugs have IC50 values for CKD4/6 in the low nanomolar range. These inhibitors bind in the cleft between the N-terminal and C-terminal lobes of the CDKs and they inhibit ATP binding. Like ATP, these agents form hydrogen bonds with hinge residues that connect the small and large lobes of protein kinases. Like the adenine base of ATP, these antagonists interact with catalytic spine residues CS6, CS7, and CS8. These and other CDK antagonists are in clinical trials for the treatment of a wide variety of malignancies. As inhibitors of the cell cycle, it is not surprising that one of their most common toxicities is myelosuppression with decreased neutrophil production.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Ciclo Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/fisiología , Humanos , Ligandos , Neoplasias/tratamiento farmacológicoRESUMEN
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.
RESUMEN
In the last 10 years, oncology has been transformed by the development and broad availability of small molecule therapies for cancer. Compounds have been and are being developed to target nearly every known relevant component of the cell's machinery. One class of compounds, the cyclin-dependent kinase (CDK) inhibitors, was originally conceived as an anticancer therapeutic based on the premise that as cancer is (in part) defined by loss of cell-cycle control, the interruption of cell cycle could arrest cancer growth. While CDKs do play critical roles in cell cycle, including in cancer, the study of CDK inhibitors in the relatively non-proliferative disease chronic lymphocytic leukemia (CLL) revealed alternate mechanisms both for CDKs, as well as for the role of CDK inhibitors in cancer therapy. In this review, we will consider three CDK inhibitors: alvocidib (flavopiridol), dinaciclib, and TG02. We will discuss their preclinical and clinical development for the treatment of CLL, and suggest that CDK inhibitors remain relevant in CLL, with potential utility in several scenarios.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Resultado del TratamientoRESUMEN
INTRODUCTION: Alvocidib, which has orphan drug designation in chronic lymphocytic leukemia (CLL) from the FDA and the EMA, is a plant-derived semisynthetic flavone that acts as a cyclin-dependent kinase inhibitor. It induces apoptosis in CLL cells in vitro and was introduced into clinical trials in CLL as an intravenous infusion in 1997, which proved disappointing. Since the drug avidly binds to plasma proteins, higher serum concentrations were required for clinical antileukemia activity than those suggested by in vitro studies. Subsequent studies utilizing bolus plus infusional doses revealed significant activity against CLL, even in patients with unfavorable characteristics. However, significant toxicity including high rates of major tumor lysis syndrome, cytokine release syndrome and secretory diarrhea were also observed. AREAS COVERED: The chemistry, pharmacodynamics, pharmacokinetics and metabolism of alvocidib are briefly discussed and phase I-II studies in CLL are discussed in detail. To date, no phase III studies in CLL have been reported. EXPERT OPINION: A number of much less toxic drugs with similar efficacy against CLL both with and without unfavorable cytogenetics have come to market. Furthermore, enthusiasm for the development of alvocidib as a single agent for the treatment of CLL has waned, primarily due to its toxicity.
Asunto(s)
Antineoplásicos/uso terapéutico , Flavonoides/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Flavonoides/efectos adversos , Flavonoides/farmacología , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Piperidinas/efectos adversos , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Then CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factors, which in turn lead to the generation of several proteins required for cell cycle progression. As a result, cells pass through the G1-restriction point and are committed to complete cell division. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S, G2, and M-phase progression. Increased cyclin or CDK expression or decreased levels of endogenous CDK inhibitors such as INK4 or CIP/KIP have been observed in various cancers. In contrast to the mutational activation of EGFR, Kit, or B-Raf in the pathogenesis of malignancies, mutations in the CDKs that cause cancers are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Abemaciclib (LY2835219), ribociclib (Lee011), and palbociclib (Ibrance(®) or PD0332991) target CDK4/6 with IC50 values in the low nanomolar range. Palbociclib and other CDK inhibitors bind in the cleft between the small and large lobes of the CDKs and inhibit the binding of ATP. Like ATP, palbociclib forms hydrogen bonds with residues in the hinge segment of the cleft. Like the adenine base of ATP, palbociclib interacts with catalytic spine residues CS6 and CS7. CDK antagonists are in clinical trials for the treatment of a variety of malignancies. Significantly, palbociclib has been approved by the FDA for the treatment of hormone-receptor positive/human epidermal growth factor receptor-2 negative breast cancer in conjunction with letrozole as a first-line therapy and with fulvestrant as a second-line treatment. As inhibitors of the cell cycle, it is not surprising that one of their most common toxicities is myelosuppression with decreased neutrophil production.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/química , Humanos , Neoplasias/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacologíaRESUMEN
There have been minimal therapeutic advancements in acute myeloid leukemia (AML) over the past 4 decades and outcomes remain unsatisfactory. Alvocidib (formerly flavopiridol) is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen, FLAM (alvocidib followed by cytarabine continuous infusion and mitoxantrone). FLAM has been evaluated in sequential phase 1 and phase 2 studies in 149 and 256 relapsed/refractory and newly diagnosed non-favorable risk AML patients, respectively, with encouraging findings in both patient populations warranting further investigation. This review highlights the mechanism of action of alvocidib, pre-clinical studies of alvocidib in AML, and the clinical trials evaluating alvocidib alone and in combination with cytotoxic agents (FLAM) in AML.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Flavonoides/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Ciclo Celular/efectos de los fármacos , Interacciones Farmacológicas , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/administración & dosificación , Flavonoides/efectos adversos , Flavonoides/farmacología , Humanos , Leucemia Mieloide Aguda/enzimología , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/análisis , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/biosíntesis , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Terapia Recuperativa , Síndrome de Lisis Tumoral/etiologíaAsunto(s)
Antineoplásicos/uso terapéutico , Bencimidazoles/clasificación , Flavonoides/clasificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Producción de Medicamentos sin Interés Comercial , Piperidinas/clasificación , Pteridinas/clasificación , Animales , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas/tendencias , Epigénesis Genética/efectos de los fármacos , Flavonoides/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/uso terapéutico , Terminología como AsuntoRESUMEN
Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.