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1.
Cancer ; 129(15): 2321-2330, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37042080

RESUMEN

BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Azacitidina/uso terapéutico , Proteínas Hedgehog , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
2.
Am J Hematol ; 98(3): 472-480, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36625066

RESUMEN

Acute myeloid leukemia (AML) is a challenging cancer in terms of achieving and maintaining long-duration remissions. Many novel therapies have been added to the standard regimen (combining cytarabine and anthracycline "7 + 3") to achieve such goals. Nilotinib is an oral multikinase inhibitor that is active against KIT tyrosine kinase, an important stem cell target. In this trial, we combined nilotinib with 7 + 3 induction (daunorubicin 60 mg/m2), high-dose cytarabine consolidation, and subsequently, if the patient was a candidate, for 2 years' maintenance therapy in patients with AML and KIT (CD117) expression. Patients were allowed to proceed to allogeneic hematopoietic cell transplantation (HCT) if deemed necessary. Our primary goal was increased complete remission rate with this combination. Thirty-four patients (with a median age 58.5 years) were enrolled on a single-arm phase II bi-institutional study; 21 (62%) patients achieved remission. The complete remission rate was 78% in evaluable patients. Thirteen of 34 (38%) patients had allogeneic HCT, all thirteen of which are still alive (100%). Common (>20%) grade 3 non-hematological toxicities included febrile neutropenia, hypophosphatemia, elevated liver enzymes, and hypertension. Only one patient (3%) died in induction due to liver failure, which was thought secondary to daunorubicin. Our current study reveals good outcomes in patients who received HCT and may warrant a larger study to confirm our findings in that specific population.


Asunto(s)
Daunorrubicina , Leucemia Mieloide Aguda , Humanos , Persona de Mediana Edad , Citarabina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide Aguda/etiología , Inducción de Remisión
3.
BMC Cancer ; 22(1): 1013, 2022 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-36153475

RESUMEN

BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).


Asunto(s)
Enfermedades Mielodisplásicas-Mieloproliferativas , Calidad de Vida , Acetonitrilos , Citidina Desaminasa , ADN/uso terapéutico , Decitabina/uso terapéutico , Humanos , Metiltransferasas , Estudios Prospectivos , Pirazoles , Pirimidinas , Pirroles , Síndrome
4.
Blood ; 131(24): 2661-2669, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29724899

RESUMEN

Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia (MLL) gene rearrangements (MLL-r) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.


Asunto(s)
Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Histonas/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Metiltransferasas/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Bencimidazoles/efectos adversos , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Metilación/efectos de los fármacos , Metiltransferasas/metabolismo , Persona de Mediana Edad , Adulto Joven
5.
Blood ; 130(14): 1644-1648, 2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28801450

RESUMEN

Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in CCND3 A change-of-function mutation in the splicing factor U2AF1 was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically.


Asunto(s)
Leucemia de Células Pilosas/genética , Mutación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ciclina D3/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos , Genómica , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , MAP Quinasa Quinasa 1/genética , Proteínas Proto-Oncogénicas B-raf/genética , Factor de Empalme U2AF/genética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Vemurafenib
6.
Invest New Drugs ; 37(4): 636-645, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30264293

RESUMEN

Malignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 years. Whole exome and transcriptome sequencing revealed a high mutational burden tumor (22 mutations/Megabase) with homozygous BRAF V600E mutation. Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Lactonas/uso terapéutico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/tratamiento farmacológico , Anciano de 80 o más Años , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Humanos , Lactonas/sangre , Lactonas/farmacocinética , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Ratones Noqueados , Mutación , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Secuenciación del Exoma
7.
Br J Cancer ; 118(12): 1580-1585, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29867224

RESUMEN

BACKGROUND: This phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma. METHODS: Part A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only). RESULTS: MTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw). CONCLUSIONS: An intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.


Asunto(s)
Lactonas/administración & dosificación , Lactonas/farmacocinética , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Lactonas/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad
8.
J Cancer Educ ; 33(3): 653-659, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-27730534

RESUMEN

A cancer diagnosis requires significant information to facilitate health care decision making, understand management options, and health care system navigation. Patient knowledge deficit can decrease quality of life and health care compliance. Surveys were distributed to attendees of the Mayo Clinic "Living with and Surviving Cancer" patient symposium January 2015. Follow-up survey was sent to participants 3 months after the symposium. Surveys included demographic data and patient-reported disease comprehension, symptom burden, desired information, and quality-of-life assessment. Demographics: 113 patients completed the pre-intervention survey. Average age was 64.7 years. Disease types included hematologic (N = 50) and solid malignancies (N = 77). Most patients self-reported adequate baseline understanding of their disease (80 %), screening tests (74 %), and monitoring tools (72 %). Lowest knowledge topics were legal issues (13 %) and pain management (35 %). Pre- and post-analysis: 79 of the initial 113 participants completed both surveys. In the post-symposium setting, durable knowledge impact was noted in disease understanding (pre 80 % vs post 92 %), treatment options (pre 60 % vs post 76 %), nutrition (pre 68 % vs post 84 %), and legal issues (pre 15 % vs post 32 %). Most patients desired increased understanding regarding disease, screening tests, nutrition, and stress and fatigue management. The level of desired information for these topics decreased in the post-symposium setting, statistically significant decrease noted in 4 of 5 topics assessed. Knowledge needs and deficit in cancer care range from disease-specific topics, social stressors, and health care navigation. A cancer patient-centered symposium can improve patient-reported knowledge deficit, with durable responses at 3 months, but patient needs persist.


Asunto(s)
Intervención Educativa Precoz , Conocimientos, Actitudes y Práctica en Salud , Neoplasias/terapia , Educación del Paciente como Asunto , Medición de Resultados Informados por el Paciente , Calidad de Vida , Estrés Psicológico/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios
9.
Lancet Oncol ; 18(10): 1317-1326, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28844816

RESUMEN

BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer.


Asunto(s)
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Seguridad del Paciente/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
10.
Lancet Oncol ; 18(8): 1061-1075, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28645776

RESUMEN

BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. FINDINGS: Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. FUNDING: Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.


Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Pirazinas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Compuestos de Anilina/sangre , Compuestos de Anilina/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Plaquetas , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Pirazinas/sangre , Pirazinas/uso terapéutico , Recurrencia , Retratamiento , Tirosina Quinasa 3 Similar a fms/metabolismo
11.
Blood ; 125(12): 1857-65, 2015 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-25624319

RESUMEN

Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.


Asunto(s)
Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Hematología/normas , Oncología Médica/normas , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/terapia , Algoritmos , Proliferación Celular , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , Cooperación Internacional , Mutación , Fenotipo , Guías de Práctica Clínica como Asunto , Encuestas y Cuestionarios , Resultado del Tratamiento
12.
J Natl Compr Canc Netw ; 14(12): 1505-1512, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27956535

RESUMEN

The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.


Asunto(s)
Anomalías Inducidas por Medicamentos/epidemiología , Fertilidad/efectos de los fármacos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Niño , Medicina Basada en la Evidencia/normas , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Embarazo , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Privación de Tratamiento
13.
Lancet Oncol ; 16(9): 1099-1110, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26296954

RESUMEN

BACKGROUND: Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. METHODS: In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). INTERPRETATION: Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. FUNDING: Astex Pharmaceuticals, Stand Up To Cancer.


Asunto(s)
Azacitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina/administración & dosificación , Decitabina , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Estadificación de Neoplasias , Pronóstico
14.
Invest New Drugs ; 33(4): 870-80, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25933833

RESUMEN

BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.


Asunto(s)
Aminopiridinas , Antineoplásicos , Neoplasias Hematológicas/tratamiento farmacológico , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas , Anciano , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Aurora Quinasas/antagonistas & inhibidores , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Azacitidina/uso terapéutico , Femenino , Neoplasias Hematológicas/metabolismo , Humanos , Masculino , Dosis Máxima Tolerada , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular
15.
Haematologica ; 100(9): 1172-9, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26022709

RESUMEN

Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Flavonoides/administración & dosificación , Flavonoides/efectos adversos , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Tasa de Supervivencia
16.
Haematologica ; 100(9): 1117-30, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26341525

RESUMEN

In the 2008 WHO classification, chronic myeloid malignancies that share both myelodysplastic and myeloproliferative features define the myelodysplastic/myeloproliferative group, which includes chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, refractory anemia with ring sideroblasts and thrombocytosis, and myelodysplastic/myeloproliferative unclassified. With the notable exception of refractory anemia with ring sideroblasts and thrombocytosis, there is much overlap among the various subtypes at the molecular and clinical levels, and a better definition of these entities, an understanding of their biology and an identification of subtype-specific molecular or cellular markers are needed. To address some of these challenges, a panel comprised of laboratory and clinical experts in myelodysplastic/myeloproliferative was established, and four independent academic MDS/MPN workshops were held on: 9(th) March 2013, in Miami, Florida, USA; 6(th) December 2013, in New Orleans, Louisiana, USA; 13(th) June 2014 in Milan, Italy; and 5(th) December 2014 in San Francisco, USA. During these meetings, the current understanding of these malignancies and matters of biology, diagnosis and management were discussed. This perspective and the recommendations on molecular pathogenesis, diagnosis and clinical characterization for adult onset myelodysplastic/myeloproliferative is the result of a collaborative project endorsed and supported by the MDS Foundation.


Asunto(s)
Neoplasias Hematológicas , Enfermedades Mielodisplásicas-Mieloproliferativas , Adulto , Femenino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Masculino , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/patología , Enfermedades Mielodisplásicas-Mieloproliferativas/terapia , Guías de Práctica Clínica como Asunto
17.
Blood ; 119(12): 2863-72, 2012 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-22267604

RESUMEN

To identify rational therapeutic combinations with cytarabine (Ara-C), we developed a high-throughput, small-interference RNA (siRNA) platform for myeloid leukemia cells. Of 572 kinases individually silenced in combination with Ara-C, silencing of 10 (1.7%) and 8 (1.4%) kinases strongly increased Ara-C activity in TF-1 and THP-1 cells, respectively. The strongest molecular concepts emerged around kinases involved in cell-cycle checkpoints and DNA-damage repair. In confirmatory siRNA assays, inhibition of WEE1 resulted in more potent and universal sensitization across myeloid cell lines than siRNA inhibition of PKMYT1, CHEK1, or ATR. Treatment of 8 acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) cell lines with commercial and the first-in-class clinical WEE1 kinase inhibitor MK1775 confirmed sensitization to Ara-C up to 97-fold. Ex vivo, adding MK1775 substantially reduced viability in 13 of 14 AML, CML, and myelodysplastic syndrome patient samples compared with Ara-C alone. Maximum sensitization occurred at lower to moderate concentrations of both drugs. Induction of apoptosis was increased using a combination of Ara-C and MK1775 compared with using either drug alone. WEE1 is expressed in primary AML, ALL, and CML specimens. Data from this first siRNA-kinome sensitizer screen suggests that inhibiting WEE1 in combination with Ara-C is a rational combination for the treatment of myeloid and lymphoid leukemias.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Citarabina/farmacología , Leucemia Mieloide/enzimología , Proteínas Nucleares/metabolismo , Fosfotransferasas/análisis , Proteínas Tirosina Quinasas/metabolismo , Western Blotting , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Fosfotransferasas/metabolismo , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
18.
Haematologica ; 99(4): 688-96, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24179152

RESUMEN

Novel combinations targeting new molecular vulnerabilities are needed to improve the outcome of patients with acute myeloid leukemia. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a short interfering RNA screen directed against cell cycle and DNA repair genes during concurrent treatment with the WEE1 inhibitor MK1775. CHK1 and ATR, genes encoding two replication checkpoint kinases, were among the genes whose silencing enhanced the effects of WEE1 inhibition most, whereas CDK2 short interfering RNA antagonized MK1775 effects. Building on this observation, we examined the impact of combining MK1775 with selective small molecule inhibitors of CHK1, ATR and cyclin-dependent kinases. The CHK1 inhibitor MK8776 sensitized acute myeloid leukemia cell lines and primary leukemia specimens to MK1775 ex vivo, whereas smaller effects were observed with the MK1775/MK8776 combination in normal myeloid progenitors. The ATR inhibitor VE-821 likewise enhanced the antiproliferative effects of MK1775, whereas the cyclin-dependent kinase inhibitor roscovitine antagonized MK1775. Further studies showed that MK8776 enhanced MK1775-mediated activation of the ATR/CHK1 pathway in acute leukemia cell lines and ex vivo. These results indicate that combined cell cycle checkpoint interference with MK1775/MK8776 warrants further investigation as a potential treatment for acute myeloid leukemia.


Asunto(s)
Proteínas de Ciclo Celular/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/genética , Proteínas Tirosina Quinasas/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/farmacología , Pirimidinas/farmacología , Pirimidinonas , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal , Ensayo de Tumor de Célula Madre
19.
Invest New Drugs ; 31(4): 1056-65, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23242862

RESUMEN

A retrospective analysis of 130 patients was conducted in a Phase I oncology clinic to assess the effect of QTc formula selection on clinical trial eligibility. QTc values were calculated from screening electrocardiograms using 7 formulae (Bazett, Fridericia, Framingham, Hodges, Mayeda, Van de Water and Wohlfart). QTc values > 470 ms for females and > 450 ms for males were used to define prolongation. Concomitant medication potential for QTc prolongation was determined using a public database (AzCert). Ineligibility rates ranged from 3.1 % to 17.7 % (Framingham: 3.1 %, Van de Water: 3.1 %, Hodges: 3.1 %, Wohlfart: 3.1 %, Fridericia: 3.9 %, Bazett: 10.8 % and Mayeda: 17.7 %). A consistent ineligibility rate was achieved by using formulae-specific thresholds. Fifty one percent of patients were taking concomitant medications with QTc prolongation potential. The proportion of concomitant medications with the potential to prolong QTc was 11.57 % (96 of 830). Uniform criteria and guidelines for selection of QTc formulae need to be developed. Formulae-specific QTc thresholds also need to be specified.


Asunto(s)
Ensayos Clínicos Fase I como Asunto , Electrocardiografía , Frecuencia Cardíaca/fisiología , Neoplasias/fisiopatología , Selección de Paciente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
20.
Expert Opin Emerg Drugs ; 18(3): 393-404, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23968379

RESUMEN

INTRODUCTION: Polycythemia vera (PV) patients suffer from disease-related constitutional symptoms, cardiovascular complications and risk of transformation into myelofibrosis and acute leukemia. AREAS COVERED: Clinical and molecular aspects and current therapies will be described to provide clinical and molecular background to understand the natural history and treatment strategies in PV. Pertinent ongoing research questions, challenges arising out of the specific disease course and biology of PV as well as challenges and opportunities for new agents in PV are addressed. A focus is placed on pegylated interferon-α formulations (PEG-INFa2a) and JAK2 inhibitors. Newest data on symptom burden and incidence and prevalence of PV and MPNs are highlighted in the context of development of PV therapies. EXPERT OPINION: Therapeutic goals in PV are to prevent vascular events, reduce symptoms and for future therapies delay/prevent disease progression. Currently available treatments such as phlebotomy, antiplatelet therapy, managing risk factors and cytoreductive therapies such as hydroxyurea (HU) and PEG-INFa2a are effective. JAK2 inhibitors recently have shown promising activity in reducing PV symptoms and spleen size and improving blood counts. Yet the influence of long-term outcome and delaying disease progression is unknown. Thus, there still remains an unmet medical need for improved therapy and symptom management in PV.


Asunto(s)
Policitemia Vera/tratamiento farmacológico , Humanos , Hidroxiurea/uso terapéutico , Interferón-alfa/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Policitemia Vera/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico
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